Childhood obesity rates in the United States have more thantripled over the past 50 years, with recent reports indicatingthat 31.9% of all children are overweight or obese.1 Obesityin childhood, particularly during adolescence, is associatedwith significant morbidity, including type 2 diabetes mellitusand hypertension, and a high risk for adult obesity and associatedrisks for diabetes mellitus and cardiovascular disease.2 Itis imperative that effective prevention and treatment modalitiesbe identified to address the epidemic of childhood and adolescentobesity.

Current standard treatment of childhood obesity is lifestylemodification, including diet and exercise.3 However, short-termprospective trials using various lifestyle modification programshave shown that effectiveness is often related to the intensityof the program, shows high intersubject variability, and haslimited longevity.4

Metformin hydrochloride is commonly used as a primary or adjunctivetreatment in obese, nondiabetic adolescents. However, thereare limited short-term data to support this therapy, and itis unclear whether any observed effects of metformin on bodymass index (BMI) are associated with changes in body compositionor insulin sensitivity. Therefore, we conducted a 48-week randomized,double-blind, placebo-controlled trial of extended-release (XR)metformin therapy in nondiabetic obese adolescents, followedby a 48-week monitoring period after completion of treatment.

We hypothesized that treatment of obese adolescents with metforminXR coupled with a lifestyle intervention would decrease BMIas compared with treatment with placebo and the same lifestyleintervention.

SETTING

The study was conducted from October 2003 to August 2007 atthe 5 clinical sites of the Glaser Pediatric Research Network,along with the Data Coordinating Center located at Children’sHospital Boston. The study was approved by the institutionalreview boards at each of the 6 centers; informed parental consentand subject assent were obtained. An external Data and SafetyMonitoring Board was involved throughout the study.

SUBJECTS

Adolescents aged 13.00 years to younger than 18 years were eligibleif they were obese (BMI95th percentile for age and sex5) butweighed less than 136 kg (the weight limit for the dual-emissionx-ray absorptiometry [DXA] table). Subjects were excluded ifthey had a previous diagnosis of diabetes mellitus, had everused a medication to treat diabetes mellitus or insulin resistance,had ever used a medication to aid in weight loss, were takingany medications known to increase metformin levels (eg, cimetidine),received recent glucocorticoid therapy, had any identified syndromeor medical disorder predisposing to obesity, had surgical therapyfor obesity, had attended a formal weight loss program withinthe previous 6 months, admitted to significant alcohol use inthe past 6 months, had elevated creatinine (>1.2 mg/dL [to convertto micromoles per liter, multiply by 88.4]) or liver enzymes(aspartate aminotransferase or alanine aminotransferase >80U/L [to convert to microkatals per liter, multiply by 0.0167])levels, had untreated disorders of thyroid function, had impairedambulation or mobility, or had ever been pregnant.

STUDY DESIGN

After clinical eligibility was confirmed, diabetes mellituswas excluded at a baseline visit (study day 0) using an oralglucose tolerance test (OGTT). Other fasting laboratory studies,DXA, and abdominal computed tomography (CT) were also performedat baseline.

The study sample was enriched for subjects with a higher likelihoodof complying with the protocol using a 4-week placebo run-inphase, during which subjects were required to attend at least2 of 3 scheduled lifestyle modification sessions and demonstrate80% compliance with daily placebo treatment (pill count) forsubsequent randomization. Subjects were then randomized 1:1to treatment with either metformin XR (Glucophage XR) or identicalplacebo tablets and instructed to take 1 tablet/d (metforminhydrochloride XR 500 mg or placebo) orally before dinner for2 weeks, then 2 tablets/d for 2 weeks, then 4 tablets/d fromweek 8 to week 52. Investigators were permitted to adjust thedose of study drug as follows. If symptoms were mild and tolerable,study drug was continued. Persistent or severe gastrointestinalor other symptoms could lead to a reduction from 4 tablets/dto 1 tablet/d; the dose was then increased by 1 tablet/d inweekly intervals until the subject achieved a tolerable doselevel of up to 4 tablets/d. Compliance was assessed at eachstudy visit by asking the patient and parent(s) how many doseswere missed during the preceding 7 days. Adverse events wererecorded at each study visit, with investigator grading of relatednessand severity.

While healthy eating was a major component of the lifestylemodification program (described later), no specific caloriegoal was assigned to the subjects. To mitigate the possibleimpact of diet modification on vitamin and calcium intake, aswell as possible effects of metformin on vitamin B metabolismand excretion,6 subjects were also instructed to take a multivitamintablet and 1000 mg of calcium carbonate daily.7 After the baselinevisit (day 0) and randomization at week 4, subjects returnedat 16, 28, 40, 52, 64, 76, 88, and 100 weeks for a physicalexamination, anthropometry, and safety laboratory studies, includinga pregnancy test for girls. The OGTT, DXA, and abdominal CTwere performed at baseline, then at 52 weeks (last dose of studydrug) and 100 weeks (completion of study).

Subjects were asked to self-identify race from the followingcategories: American Indian or Alaska Native, Asian, NativeHawaiian or other Pacific Islander, black or African American,white, or other. Hispanic or Latino ethnicity was also voluntarilyself-identified.

LIFESTYLE INTERVENTION

All subjects were prescribed a lifestyle intervention programto increase physical activity level and optimize dietary intake.To decrease variability across sites, we selected the Weighof Life LITE8 program developed at Texas Children’s Hospital,Houston. Beginning with the run-in period, subjects were expectedto attend 10 individualized “intensive” sessions at weekly intervals,following a specific curriculum. Monthly follow-up sessionswere conducted for the remainder of the study. A trained healthspecialist led the sessions and parents/guardians were invitedto attend.

ANTHROPOMETRY

At each visit, height was measured twice using a calibrated,wall-mounted stadiometer and weight was measured twice usinga calibrated electronic scale. A third reading was taken ifthe difference between the first 2 readings was more than 0.5cm for height or more than 0.3 kg for weight. Body mass indexwas calculated as the mean weight in kilograms divided by themean height in meters squared2 and converted to a sex- and age-specificz score.5 Waist circumference was measured as the smallest circumferencebelow the rib cage and above the umbilicus.9 Tanner breast (female),genital (male), and pubic hair (both sexes) staging was assessedby an experienced clinician at each visit.

RADIOLOGICAL PROCEDURES

Abdominal CT scans were performed to evaluate abdominal fatcontent and distribution, using a modification of publishedmethods.10 The slice was aligned with the L4-L5 intervertebraldisc to the nearest millimeter using a low-dose abdominal scoutradiograph, and cross-sectional areas (in centimeters squared)for intraperitoneal and subcutaneous fat were determined usingsoftware available on the CT review console. Percentage of bodyfat and lean body mass were measured by whole-body DXA.11

LABORATORY STUDIES

A 3-hour OGTT (75-g glucose) was performed after 3 days of a150 g/d or more carbohydrate diet and a 10-hour overnight fast.Plasma insulin and glucose levels were measured at 0 (beforeglucose bolus), 15, 30, 60, 90, 120, and 180 minutes. Lipidprofiles and other laboratory test levels were measured in thefasting sample. Insulin was measured by 2-site immunochemiluminometricassays with sensitivities of 0.6 µU/mL. Safety laboratorytests included hematology and chemistry panels. All assays wereperformed at Esoterix Clinical Trials Services (Calabasas Hills,California).

where FI is the fasting insulin level, FBG is the fasting glucoselevel, and MI and MG are the mean insulin and glucose levelsmeasured between 0 and 120 minutes during the OGTT.

Beta-cell activity was estimated using the corrected insulinrelease at the glucose peak14 calculated as

where Ggp is the peak glucose level (maximum of all 7 measures[0-180 minutes]) and Igp is the insulin concentration at thetime of the glucose peak.

RANDOMIZATION AND BLINDING

Subjects who successfully completed the run-in period were randomizedto metformin XR or placebo treatment according to random sequencesconstructed at the Data Coordinating Center. To ensure balanceacross major factors, the randomization was stratified by siteand sex. Subjects and study personnel were blinded to assignmentthroughout the entire study. To ensure nonpredictability ofassignment, the randomization sequence was grouped in randomlypermuted blocks of 2 and 4, and assignments were randomly permutedwithin block. Study drugs were prepared so as to be indistinguishableand labeled with a unique but uninformative code. The Data CoordinatingCenter maintained the key to drug codes for use during unblindingas needed for safety concerns (eg, in 2 cases of pregnancy)and for the data analyses.

STATISTICAL ANALYSIS

The intention-to-treat principle was used, analyzing each subjectas part of his or her assigned treatment group, regardless ofcompliance. All analyses used 2-tailed tests with P = .05as the critical value for statistical significance. SAS software(version 9.1; SAS Institute Inc, Cary, North Carolina) was usedfor all computations.

Between-group comparisons of baseline characteristics used the2 test for dichotomous and polytomous variables, corroboratedin cases of sparse data by the Fisher exact test, and the 2-samplet test for continuous measures, corroborated in cases of severelyskewed distribution or markedly unequal variance by the Wilcoxon2-sample test. The same methods were used to compare baselinecharacteristics between those who completed the 52-week primaryassessment and those who dropped out.

To test for biased dropout, we performed a logistic regressionanalysis to test whether BMI on a particular visit was associatedwith dropout before the following visit. In a second set ofanalyses, we tested for association between baseline variables(including BMI) and completion of the week 52 visit.

The repeated-measures analysis comprised all available measurementson all randomized subjects, including withdrawals and dropoutsas well as completers, through the last visit for those whowithdrew or were lost to follow-up. This analysis is unbiasedunder the assumption of missingness at random, ie, likelihoodof missing data related only to variables included in the model.15 For corroboration, we imputed the missing data in 2 ways,both conservatively biased toward the null hypothesis of nodrug effect: return to baseline BMI or last observation carriedforward. In both cases, intermittent missing values were imputedwith the last prior observation.

An interim analysis was performed and presented to the Dataand Safety Monitoring Board after 50% of subjects had reachedthe 52-week primary evaluation point, for purposes of assessingsafety and progress. Unblinded data were seen only by the Dataand Safety Monitoring Board and study statistician. There wereno plans to stop the study for early success or lack of powerbased on the interim results, as it was expected that all subjectswould be enrolled by that time. Consequently, no adjustmentwas made to the critical P value for final analysis of the primaryend point.

POWER AND SAMPLE SIZE

To estimate power, we analyzed a simulated sample with 15% AfricanAmerican and 15% Hispanic subjects, balanced by sex, with 20%attrition and a bias induced by selective dropout.16 Assumingan SD of 1.9 for BMI change,17 an enrolled sample of 72 provided80% power to detect a differential of 1.46 between treatmentarms or between sexes and 1.75 between white subjects and others.The final randomized sample was 77, owing to simultaneous successfulrun-ins at different sites in the final weeks of recruitment.

Ninety-two subjects were screened and 77 were randomized, 39to metformin XR, 38 to placebo; 27 and 19 in each group weremeasured at weeks 52 and 100, respectively (Figure 1). For therandomized participants, there were no between-group differencesin baseline characteristics (Table 1). During the treatmentperiod, the odds of dropping out after any particular visitincreased by a factor of 1.15 per unit BMI at that visit, butthat rate did not differ between metformin and placebo subjects.The 23 subjects not measured at week 52 had a higher mean (SE)baseline BMI compared with the remaining 54 subjects (37.8 [1.1]vs 35.1 [0.7]; P = .04); however, the influence ofBMI on dropout did not differ between the 2 treatment arms (P = .63)for treatment x completion interaction and no otherbaseline characteristic had an influence on the likelihood ofdropout. One subject withdrew from the study after week 16 butreturned for measurement at week 100. There were 2 pregnancies(1 each, metformin and placebo groups) resulting in discontinuationfrom study.

Figure 1. Disposition of subjects. “Withdrew” refers to withdrawal of consent. One subject in the metformin hydrochloride extended release group withdrew consent at week 16 but returned for a measurement at week 100 (end of study). See text for further details.

Figure 2. Body mass index (BMI) (calculated as mean weight in kilograms divided by mean height in meters squared) (A) and adjusted change in BMI from baseline (B) (see text for further details). Data are plotted as the mean and 1 SE. Vertical dotted lines separate the study drug treatment (4-52 weeks) and post–study drug treatment (52-100 weeks) monitoring periods. Part A includes data for the run-in period (0-4 weeks). Metformin was given as metformin hydrochloride extended release.

SUBGROUP ANALYSIS

Neither sex, race, nor ethnicity significantly modified themetformin effect on BMI found in the entire group (P > .20for interaction in repeated-measures analysis). The treatmenteffect did not vary by study center, parental education, orfamily history of type 1 or type 2 diabetes (P > .10).Likewise, baseline fasting insulin level, OGTT insulin response,composite insulin sensitivity index, and HOMA-IR did not modifythe effect in the full sample or when restricted to white race.

SECONDARY OUTCOMES

Among the secondary measures of obesity, BMI z score and DXAfat mass revealed similar changes to BMI, although the meanadjusted difference between the 2 groups did not reach statisticalsignificance. Only BMI z score showed a P value less than .10.Metformin XR treatment had no significant impact on DXA fatmass, DXA lean mass, CT intraperitoneal fat area, CT subcutaneousfat area, CT intraperitoneal fat, abdominal fat by CT, or CTintraperitoneal fat to subcutaneous fat ratio (Table 2). Likewise,metformin XR had no significant impact on HOMA-IR; the areaunder the insulin curve; the area under the glucose curve; compositeinsulin sensitivity index; corrected insulin release at theglucose peak; levels of low-density lipoprotein cholesterol,triglycerides, or high-density lipoprotein cholesterol; or thetriglycerides to high-density lipoprotein cholesterol ratio.

SECOND YEAR

The BMI difference between the groups persisted for 12 to 24weeks after cessation of study drug (Figure 2) (Table 2). Thereafter,the mean BMI in the metformin group increased toward that inthe control group.

COMPLIANCE WITH INTERVENTION

Compliance with medications was good and similar in both groups(mean [SD] number of missed doses per week, 1.2 [1.7] metforminvs 1.3 [3.5] control; P = .29). Likewise, the mean[SD] number of the lifestyle modification sessions attendedwas similar in both groups (6.3 [3.1] metformin vs 6.7 [3.3]control; P = .38). Neither the estimate of the numberof missed doses nor the number of lifestyle sessions attendedwere associated with the change in BMI in the metformin group.

SAFETY

During weeks 4 to 52, the safety population consisted of allsubjects who received at least 1 dose of study drug. Duringweeks 52 to 100, the safety population included all subjectswho had at least 1 visit during this period.

During weeks 4 to 52, the following adverse events occurredat least once in 5% or more of subjects in either group and5 or more percentage points greater in 1 group relative to theother (metformin vs placebo): headache (n = 12 [31%]vs 8 [21%]), nausea (n = 9 [23%] vs 3 [8%]), vomiting(n = 6 [15%] vs 1 [3%]), upper respiratory tract infection(n = 18 [46%] vs 23 [61%]), and musculoskeletal complaints(n = 5 [3%] vs 7 [18%]). There was no statisticallysignificant difference between the metformin and placebo groupsin the incidence of any particular class of adverse events.Two events of nausea in 2 metformin-treated subjects were consideredprobably related; 1 subject discontinued taking the study drug.Two subjects in the metformin group and 1 in the placebo grouphad elevated alanine aminotransferase levels before week 52and discontinued taking the study drug. There was 1 severe adverseevent (appendectomy, metformin group) considered unrelated tothe study drug; all other adverse events were mild or moderate.In total, the dose of study drug was decreased during weeks4 to 52 for 6 subjects in the metformin group and 3 in the placebogroup.